tbuckley/cabot-search huggingface dataset:
Abstract 2058: Identifications of novel variants using system biology-based approaches in NT5C2, its association to relapse acute lymphoblastic leukaemia
Authors: Sugunakar V, Obul Reddy Bandapalli, Ramita Sharma
Journal: Cancer Research (2023)

Abstract Acute Lymphoblastic Leukaemia (ALL) patients experience relapse despite having a good prognosis; approximately 90% of children and 75% to 85% of adolescents and young adults survive for five years. Chemotherapy resistance and a poor prognosis are linked to relapsed acute lymphoblastic Leukaemia (R-ALL). Evidence suggests that the cytosolic 5 nucleotidase II (NT5C2) gene mutations play a crucial role in the emergence of recurrent ALL; The early R-ALL is usually accompanied by 6-MP resistance, which is typically brought on by gain-of-function mutations impacting NT5C2-driven mutation in relapse mutations by different mechanisms is still unknown. The study aims to identify novel top missense variants of NT5C2 that play a crucial role in the resistance of chemotherapy drugs, altered biological pathways and their impact on the treatment of relapse leukaemia. NT5C2 (5'-Nucleotidase, Cytosolic II) is a Protein Coding gene. This gene induces resistance to chemotherapeutic drug 6 mercaptopurine Which causes leukaemia cell growth and leukaemia-initiating cell activity. The NT5C2 gene variants are extracted from Genome Aggregation Database (gnomAD) and ExAC. The extracted data contained 2280 variants with chromosome number, position reference allele, and altered allele and these were functionally annotated using the ANNOVAR tool. The variants are screened through various computational tools to narrow down based on non-synonymous and stopgain mutations in the exonic region. The predicted 519 variants narrow down by scoring GERP (&amp;gt;2.0) and CADD PHRED (cut-off score &amp;gt;10), ClinVar, SIFT score, Polyphen, PhyloP, PhastCons, LRT score predictions and which indicates the top 10% deleterious variants including reported and unknown variants. The SNPs, insertions, deletions, CNVs or structural variants of top missense variants on genes, transcripts, and protein sequence determined on Variants Effect Predictor on the ensemble. These variants were verified on dbSNP and Clinvar through their variant IDs. The functional prediction of these variants was made to detect their significant role in R-ALL. These findings examine the future role of NT5C2 mutations in the chemoresistance of relapse ALL. This may help to find a new therapeutic combination of drugs to treat relapse acute lymphoblastic leukaemia to improve overall survival. Citation Format: Sugunakar V, Obul Reddy Bandapalli, Ramita Sharma. Identifications of novel variants using system biology-based approaches in NT5C2, its association to relapse acute lymphoblastic leukaemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2058.
Abstract 3173: Integrative structural models of oncogenic mutants within the trans- and juxta-membrane region of human epidermal growth factor receptors (HERs)
Authors: Christina Mercado, Abdullah Al Mamun, Younghee Park, Christine M. Lovly, Jens Meiler, Kaitlyn Ledwitch
Journal: Cancer Research (2023)

Abstract The trans- and juxtamembrane domains (TMD/JMD) of human epidermal growth factor receptors (HER/EGFR/ErbB) regulate the helix-helix dimerization interface to control receptor tyrosine kinase (RTK) activation. Patient-identified non-small cell lung cancer (NSCLC) mutations occur all along the EGFR (HER1) and HER2 TMD and JMD, but our structural understanding of how these patient-derived TMD/JMD mutations hijack wild-type RTK function to drive cancer is lacking. In this work, we integrate tools in experimental biophysics and computational modeling to evaluate the structural mechanism(s) driving these interactions in atomic detail. We use nuclear magnetic resonance (NMR) spectroscopy to assess how oncogenic mutations within the TMD/JMD perturb the architecture/interactions of the dimer interface. NMR-derived models are used to seed molecular dynamics (MD) simulations to probe how mutations affect TMD association and activation/stabilization via dimerization in a realistic membrane environment. We apply this strategy and focus our initial efforts on the EGFRA647T variant. We computed the free energy landscape from our simulations and show that the active state for the EGFRA647T-HER2WT heterodimer is stabilized by 10 kcal/mol. Conversely, the wild-type EGFR-HER2 heterodimer is stabilized by 5 kcal/mol for the inactive state suggesting the propensity of the EGFRA647T mutant favors the active state. These results are part of a multidisciplinary collaboration that share the common goal of constructing holistic models that detail how TMD/JMD variants are aberrantly activated in cancer. Citation Format: Christina Mercado, Abdullah Al Mamun, Younghee Park, Christine M. Lovly, Jens Meiler, Kaitlyn Ledwitch. Integrative structural models of oncogenic mutants within the trans- and juxta-membrane region of human epidermal growth factor receptors (HERs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3173.
Abstract 3175: Comprehensive multi-omic characterization of hepatocellular carcinoma in Hispanic patients
Authors: Debodipta Das, Xiaojing Wang, Yu-Chiao Chiu, Hakim Bouamar, Yidong Chen, Siyuan Zheng, Francisco G. Cigarroa, Lu-Zhe Sun
Journal: Cancer Research (2023)

Abstract Hispanics in the US experience a disproportionate burden of hepatocellular carcinoma (HCC) with an overall incidence and cancer-related mortality nearly two times higher than non-Hispanic whites. The genomic characteristics and underlying molecular mechanisms driving tumorigenesis associated with HCC in Hispanic patients remain unknown. Here, we used 31 paired tumor and adjacent non-tumor liver samples from Hispanic patients in South Texas to perform integrated genomic, transcriptomic, proteomic, and metabolomic analyses. Similar to HCC in other ethnic groups, CTNNB1 and TP53 were found to have the most frequent somatic mutations in the Hispanic HCC. On the other hand, AXIN2 and to a lesser degree MTOR appear more frequently mutated in the Hispanics compared to the various ethnic groups included in The Cancer Genome Atlas (TCGA) study. Somatic mutations in the Hispanic HCC showed signatures of tobacco chewing and aflatoxin exposure, which are different from the signatures found frequently in the liver cancer patients in the TCGA study. The WNT, TP53, &amp; cell cycle were the most frequently altered oncogenic pathways in our cohort. Unsupervised clustering of patients, based on the enrichment scores from single sample Gene Set Enrichment Analysis (ssGSEA) using our tumor and nontumor paired RNA-Seq and proteomic data, revealed two clusters with striking differences in various signaling pathways and cellular functions. A similar clustering pattern with a significant difference in overall survival was seen in the patients from the TCGA study. Irrespective of ethnicity, immune infiltration in the tumor microenvironment and liver function-related pathways were significantly different between patients in these clusters. Integrated transcriptomic, proteomic, and metabolomic analyses identified significant negative enrichments in gluconeogenesis, TCA cycle, and glutamate metabolism in Hispanic HCC. These results suggest the existence of molecular mechanisms either unique in Hispanics or similar to non-Hispanic HCC, especially from the TCGA study. Our findings might provide insights to developing predictive biomarkers for the early diagnosis and novel therapeutics for the management of HCC. Citation Format: Debodipta Das, Xiaojing Wang, Yu-Chiao Chiu, Hakim Bouamar, Yidong Chen, Siyuan Zheng, Francisco G. Cigarroa, Lu-Zhe Sun. Comprehensive multi-omic characterization of hepatocellular carcinoma in Hispanic patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3175.
Abstract 5059: High-throughput monitoring of proteoforms and pathways through multiplexed and customizable mass spectrometry assay panels
Authors: Sebastian Müller, Véronique Laforte, Simonas Savickas, Maik Müller, Yuehan Feng, Lukas Reiter
Journal: Cancer Research (2023)

Abstract Proteins represent a key class of analytes in pharmacodynamic (PD) analysis, an essential component in preclinical and clinical studies which inform about a biological system’s response to drug treatment. Pharmacodynamic signatures typically comprise target engagement marker and downstream pathway markers. With recent development in targeted therapies and novel therapeutic modalities such as protein degraders, the scope of PD has widened to cover predictive and stratification biomarkers which can inform patient selection and contribute to further understanding of potential drug resistance. Using peptides as surrogate for proteins of interest, mass spectrometry (MS)-based approach alleviates the barriers of reagent specificity of antibody-based methods which can be affected by species and matrices used in preclinical drug development. Moreover, the use of stable-isotope labeled standard (SIS) reference peptides grants targeted MS assays unraveled specificity and the ability to determine absolute quantity of a given analyte. Harnessing the power of targeted MS, we present an oncology-focused assay repository which contains 804 peptides corresponding to 582 proteins. All 804 peptide surrogates were chosen under strict selection criteria such as uniqueness/proteotypicity and stability. Off-the-shelf availability (PQ500 kit) of SIS reference peptides for all 582 proteins facilitates the deployment of any of these assays in a plug-and-play manner. The collection of 582 protein targets cover &amp;gt; 180 cellular pathways (Reactome pathways e.g. cytokine signaling, cell-cell communication, activation of matrix metalloproteinases) together with 49 FDA-approved drug targets. To further evaluate the performance of these assays, we carried out a case control study comprising plasma samples from 5 patient groups (lung, colorectal, pancreatic, breast and prostate cancer) and age and gender-matched healthy subjects. In total, we measured absolute quantities of 582 proteins across 180 plasma samples while validating the expression profiles of well-characterized biomarkers in patient plasma. To conclude, we’ve demonstrated the application of targeted MS approach for the routine analysis of pharmacodynamic biomarkers. Its multiplexing capability, together with the adaptability to various species allow this method to maneuver through preclinical and clinical scenarios. Citation Format: Sebastian Müller, Véronique Laforte, Simonas Savickas, Maik Müller, Yuehan Feng, Lukas Reiter. High-throughput monitoring of proteoforms and pathways through multiplexed and customizable mass spectrometry assay panels. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5059.
Abstract 240: Comprehensive analytical solution to measure HRD genomic scars from SNP arrays, pan-cancer NGS panels, and optical genome mapping (OGM)
Authors: Daniel Saul, Megan Roytman, Viren Wasnikar, Rachel Burnside, Alex Hastie, Alka Chaubey
Journal: Cancer Research (2023)

Abstract Homologous recombination deficiency (HRD) status has been shown to be an effective pharmacogenetic biomarker for determining the efficacy of PARP inhibitor therapy across various tumor types. A functional assessment of the genomic instability associated with HRD is critical as more than half of HRD positive tumors do not have a known causative mutation. Genomic instability is commonly achieved through assessment of three characteristic genomic scars: Loss of heterozygosity (LOH), Telomeric Allelic Imbalance (TAI), &amp; Large-Scale State Transitions (LST) but is challenging due to the need for robust detection of copy number and allelic events genome-wide. As the technology commonly used to analyze tumors varies, we sought to compare the concordance of commonly used platforms to measure genomic instability. Bionano VIA™ software provides a standardized analytical measurement of the genomic scars across technologies, including SNP arrays, pan-cancer gene panels, and optical genome mapping (OGM). The software is uniquely capable to profile solid tumors from pan-cancer sequencing panels, such as the Illumina TruSight Oncology 500 (TSO500) panel, by employing a dynamic binning approach of sequencing data to detect copy number variant (CNV) and LOH events. OGM can detect additional classes of structural rearrangements missed by other technologies to provide new insights into genomic instability. In this study, tumor samples were run on multiple technologies and analyzed in VIA to provide a measurement of the genomic scars. A comparative analysis of each technology’s performance to detect genomic instability through a standardized analytical approach will be described to provide insight into the most effective technologies to assess HRD. Citation Format: Daniel Saul, Megan Roytman, Viren Wasnikar, Rachel Burnside, Alex Hastie, Alka Chaubey. Comprehensive analytical solution to measure HRD genomic scars from SNP arrays, pan-cancer NGS panels, and optical genome mapping (OGM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 240.
Abstract 1137: Identification of a high selective SMARCA2 degrader which effectively suppresses the SMARCA4-deficient tumors <i>in vitro</i> and <i>in vivo</i>
Authors: Feng Zhou, Zhiyong Yu, Ruonan Chen, Feng Tang, Peng Gu, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang
Journal: Cancer Research (2023)

Abstract The SWI/SNF chromatin-remodeling complex plays essential roles in a variety of cellular processes including differentiation, proliferation and DNA repair. Mammalian SWI/SNF complexes always contain one of two mutually exclusive and structurally highly related ATPases: SMARCA2/BRM or SMARCA4/BRG1, as its catalytic subunit, which hydrolyze ATP to drive nucleosome movement. It is reported that absence of SMARCA4 are present in several cancers and these SMARCA4 deficient cells highly depend on its paralog SMARCA2 for survival. Furthermore, concurrent inhibition of SMARCA2 and SMARCA4 is fatal to normal cells. Therefore, it holds great therapeutic promise to treat SMARCA4 deficient cancers with selective SMARCA2 degraders while leaving SMARCA4 wild type cells unaffected. Here, we report that SCR-9140 is a high selective SMARCA2 degrader which demonstrates superior anti-tumor activity and low cytotoxicity against non-malignant cells. SCR-9140 strongly degrades SMARCA2 with DC50 of &amp;lt;1 nM and achieves the complete protein degradation (Dmax of &amp;gt;95%) and also shows 100-fold degradation selectivity over SMARCA4 with DC50 of around 100 nM and Dmax of &amp;lt;60% in HiBiT knock-in SW1573 cells. Across a panel of SMARCA4 deficient tumor cell lines, SCR-9140 potently inhibits proliferation with IC50 values ranging from 1 to 50 nM. Due to the high selectivity over SMARCA4, SCR-9140 neither inhibits proliferation of SW1573 (SMARCA2-WT SMARCA4-WT) cells nor NCI-H1581 (SMARCA2-DEL SMARCA4-DEL) cells with IC50s of over 2000 nM. The degraders with poor selectivity of SMARCA2/4 (DC50 ratio: &amp;lt; 10 folds, Dmax of SMARCA4 &amp;gt; 80%) strongly inhibit the SW1573 cells proliferation with IC50s &amp;lt; 100nM, while there are no significant effects on the NCI-H1581 cells ascribing to the absence of targets. Furthermore, SCR-9140 demonstrates weak cytotoxicity on non-malignant cells, such as WI-38 (human lung fibroblast cells), THLE-2 (human liver cells), and human PBMC, rendering it the greater therapeutic window. In a CDX model of NSCLC, SCR-9140 effectively inhibits tumor growth and TGI correlates well with SMARCA2 degradation in tumors. In conclusion, our potent and selective SMARCA2 degrader, SCR-9140 induces strong synthetic lethality in SMARCA4 deficient cells in vitro and in vivo and shows great safety margin in normal cells. Citation Format: Feng Zhou, Zhiyong Yu, Ruonan Chen, Feng Tang, Peng Gu, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Identification of a high selective SMARCA2 degrader which effectively suppresses the SMARCA4-deficient tumors in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1137.
Abstract 1095: Exploiting altered methionine metabolism to overcome treatment resistance in glioblastoma
Authors: Navyateja Korimerla, Kari-Wilder Romans, Peter Kalev, Ayesha Kothari, Nathan Qi, Charles Evans, Maureen Kachman, Marc L Hyer, Katya Marjon, Taryn Sleger, Daniel R Wahl
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor and is uniformly fatal due to resistance to standard therapies such as radiation (RT) and chemotherapy. Our group and others have identified altered metabolism as a key mediator of GBM RT resistance. Methionine is an essential sulfur-containing amino acid that cells use to synthesize antioxidants, polyamines and S-adenosyl methionine (SAM), which drives intracellular methylation reactions. Methionine uptake is dramatically elevated in GBM compared to normal brain, but what GBMs use this methionine for, and whether it governs GBM treatment resistance, is unknown. Here, we find that RT acutely increases the levels of numerous methionine-related metabolites in multiple RT-resistant GBM models. To interrogate metabolic pathway activity, we used 13C5 methionine stable isotope tracing to show that GBMs respond to RT by activating the conversion of methionine to SAM, which is dependent on signaling through the DNA damage response. We developed in vivo methionine stable isotope tracing techniques to confirm these findings in orthotopic PDX models of GBM. Blocking the conversion of methionine to SAM, through pharmacologic inhibition of methionine adenosyltransferase 2A (MAT2A), slowed the repair of RT-induced DNA damage and increased cell death in GBM models following RT. These effects were especially pronounced in GBM models lacking the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP). Pharmacologic inhibition of MAT2A in flank and orthotopic in vivo GBM models depleted SAM levels and slowed tumor growth when combined with RT. Combining MAT2A inhibition with dietary methionine restriction and RT slowed GBM tumor growth even further. Together, our work demonstrates a new signaling link between DNA damage and methionine-driven SAM synthesis in GBM. Inhibiting SAM synthesis slows the repair of RT-induced DNA damage and augments RT efficacy. This therapeutic strategy may be especially effective in GBMs defective in methionine salvage and spare normal cortex in which methionine salvage is active. Citation Format: Navyateja Korimerla, Kari-Wilder Romans, Peter Kalev, Ayesha Kothari, Nathan Qi, Charles Evans, Maureen Kachman, Marc L Hyer, Katya Marjon, Taryn Sleger, Daniel R Wahl. Exploiting altered methionine metabolism to overcome treatment resistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1095.
Abstract 1019: Altona regression model: a new prognostic model for breast cancer patients after neoadjuvant treatment
Authors: Anne-Sophie Wegscheider, Katharina Lotfy-Eckmann, Bernhard Ulm, Christoph Lindner, Kay Friedrichs, Axel Niendorf
Journal: Cancer Research (2023)

Abstract The purpose of the study was to create a new prognostic model for breast cancer (BC) patients that had been treated with a preoperative neoadjuvant chemotherapy, considering different parameters of regressive changes in the residual tumor (RT) respectively the tumor bed (TB). HE-stained whole-slide images of 518 patients, treated between 2001-2019 in Hamburg, Germany following current therapy standards, were analyzed regarding different variables of regressive changes in the pretherapeutic diagnosed BC. First, size of RT and TB was measured, lymph node metastasis and residual intraductal carcinoma in situ were noted. Additional parameters that were examined were cell density and cell shape of RT, heterogeneity of residual tumor cells spreading within the TB and size of the biggest cell clusters as well as changes of the stroma and inflammation within the TB. Data were used pseudo-anonymized after consent was given by the patients and a positive vote of the ethics committee. In the univariate observation of above-mentioned variables it was shown that heterogeneity, cell density and cell shape of residual tumor cells, stroma changes and the presence of lymph node metastases as well as largest diameter and largest cluster of RT have an impact on progression free survival. Using decision tree analysis, the patient cohort could be divided in three risk groups with significant different outcome regarding progression free survival with low, intermediate and high risk for an event (local recurrence of disease, metastasis, death). Our multivariate "Altona regression model", that was constructed using Cox regression, showed significantly better prognostic value concerning progression free survival for BC patients after neoadjuvant therapy and following surgery, compared to two well-known regression gradings by Sinn et al. and MD Anderson (RCB). Comparison of regression models Altona Sinn et al. RCB Altona vs. Sinn Altona vs. RCB Sinn vs. RCB iAUC 0.607 0.350 0.380 &amp;lt; 0.001 &amp;lt; 0.001 &amp;lt; 0.001 Concordance 0.788 0.378 0.478 &amp;lt; 0.001 &amp;lt; 0.001 &amp;lt; 0.001 Citation Format: Anne-Sophie Wegscheider, Katharina Lotfy-Eckmann, Bernhard Ulm, Christoph Lindner, Kay Friedrichs, Axel Niendorf. Altona regression model: a new prognostic model for breast cancer patients after neoadjuvant treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1019.